It is without question that nerve agents, such as sarin and other organophosphates, pose one of the most serious threats of attack to human populations, particularly from terrorist groups. This is due in part to the ease with which nerve agents can be synthesized, concealed and transported, and of course to their potential for resulting in mass casualties. Unfortunately, many countries and their military forces still stockpile these nerve agents.
Seizures are the most treatment-refractory complication of nerve agent intoxication, and were a prominent feature in the Tokyo subway attacks (Nozaki et al., 1995, Lancet 345:980-981). These seizures turn into uncontrolled status epilepticus (SE), refractory to treatment with antiepileptic drugs (Shih et al., 1999, J Biomed Sci 6:86-96) and cause severe brain damage (Shih et al., 1999, J Biomed Sci 6:86-96; McDonough, 2002, Military Psychol 14:93-119; Joosen et al., 2009, Neurotoxicology 30:72-80) and chronic epilepsy (Pernot et al., 2009, Neuroscience 162:1351-65; de Araujo Furtado et al., 2010, Epilepsia 51:1503-10).
Soldiers and civilians exposed to nerve agents are currently treated with antidote kits such as Mark I (Atropine sulfate and Pralidoxime) and CANA (Diazepam). When injected within minutes of nerve agent exposure, these two injections can prevent or reduce the seizures. However, once seizures start, they become quickly resistant to the treatments. The seizures generated by these organophosphates quickly become self-sustaining, independent of their original cholinergic trigger, and refractory to standard treatment (benzodiazepines), and represent an unresolved problem to this very serious military and terrorist threat.
In addition, routine status epilepticus encountered in hospital emergency rooms as a result of many causes, such as due to head trauma, epilepsy, infection, stroke, drug abuse or withdrawal, shares many features in common with SE triggered by nerve agents. It also tends to become self-sustaining, pharmacoresistant and independent of its original cause (Wasterlain, and Treiman, 2006, from Status Epilepticus: Mechanisms and management. MIT Press, Boston; Mazarati et al., 1998, Brain Res 814:179-185; Wasterlain et al., 2000, Epilepsia 41:134-143; Chen and Wasterlain, 2006, Lancet Neurology 5:246-256).
Monotherapy is widely accepted as the current best option for treatment of epilepsy, and controlled studies of the treatment of status epilepticus (SE) have shown lorazepam monotherapy to be as effective as any treatment tested (Treiman et al., 1998, New Engl. J. Med 339:792-798). However, the major reasons for preferring monotherapy in the treatment of chronic epilepsy, such as minimizing lifelong exposure to potentially toxic drugs, may not apply to SE, an acute, life-threatening event of limited duration. There is a paucity of experimental or clinical evidence supporting the superiority of monotherapy in the treatment of acute seizures and SE. There is also no consensus on the criteria which allow comparisons between the benefits and adverse effects of mono- and polytherapy.
Many animal models of SE have previously been developed (Wasterlain, 1974, Epilepsia 15:155-176; Wasterlain, 1976, Neurology 26:975-986; Fujikawa, et al., 1989, Amer J Physiol 256:C1160-C1167; Thompson, et al. 1997, Brain Research 100:1-4; Mazarati, et al., 1998, Brain Res 814:179-185; Mazarati, et al., 1998, J. Neurosci 18:10070-10077; Mazarati, et al., 1998, Brain Res. 801:251-253; Suchomelova, et al., 2006, Ped. Res. 59:237-243), which have elucidated many of the mechanisms involved in the development of that condition (Wasterlain, et al., 1972, Brain Res 39:278-284; Dwyer, et al., 1980, J Neurochem 34:1639-1647; Wasterlain, et al., 1984, Proc Natl Acad Sci USA 81:1253-1257; Bronstein, et al., 1988, Neurochem Res 13:83-86; Wasterlain, et al., 1993, Epilepsia 34:S-37-S53; Wasterlain, et al. Neurochem Res 18:527-532; Mazarati, et al., 1998, Brain Res 814:179-185; Mazarati, et al., 1998, J. Neurosci 18:10070-10077; Mazarati, et al., 1998, Brain Res. 801:251-253; Liu, et al., 1999, Proc Natl Acad Sci 96:5286-5291; Wasterlain, et al., 2000, Epilepsia 41:134-143; Lopez-Meraz et al., 2010, Epilepsia 51:56-60). An experimental model of pharmacoresistance to benzodiazepines (the standard treatment for SE) during SE has previously been described (Mazarati, et al., 1998, Brain Res 814:179-185; Mazarati, et al., 1998, J. Neurosci 18:10070-10077; Mazarati, et al., 1998, Brain Res. 801:251-253). Several books on SE have been published (Delgado-Escueta, et al., 1983, from Status Epilepticus: Mechanisms of Brain Damage and Treatment, Raven Press, N.Y.; Wasterlain and Vert, 1990, from Neonatal Seizures. Raven Press, New York; Wasterlain, et al., 2006, from Status Epilepticus: Mechanisms and management. MIT Press, Boston).
Recent studies have shown that seizure-induced trafficking of synaptic GABAA and glutamate receptors causes both a failure of GABAergic inhibition and an increase in glutamatergic excitation during SE (Mazarati, et al., 1998, Brain Res 814:179-185; Mazarati, et al., 1998, J. Neurosci 18:10070-10077; Mazarati, et al., 1998, Brain Res. 801:251-253; Naylor, et al., 2005, J Neurosci 25:7724-7733; Goodkin, et al., 2008, J Neurosci 28:2527-38; Wasterlain, et al., 2002, Ann. Neurol. 52(S1):516).
Recent work has demonstrated that during experimental SE in the rat, the initiation of self-sustaining seizures during SE and the development of pharmacoresistance to benzodiazepines result in part from the seizure-associated internalization of synaptic GABAA receptors in key brain regions (Naylor, et al., 2005, J Neurosci 25:7724-7733). The internalization of synaptic GABAA receptors results in temporary inactivation of those receptors, which decreases inhibition at a time when the brain needs it most and explains in part why seizures become self-sustaining. It also reduces the potency of drugs such as benzodiazepines, which act on those receptors. With fewer active synaptic receptors to bind to, the therapeutic effect of these drugs is significantly reduced. The maintenance of self-sustaining seizures during SE is also in part due to seizure-induced trafficking of NMDA receptors from cytosol to the synaptic membrane, which increases the number of NMDA receptors per synapse during SE (Naylor, et al., 2003, Society for Neuroscience abstract viewer and itinerary planner: 345.4; Wasterlain, et al., 2002, Ann. Neurol 52:S16; Wasterlain, et al., 2009, Epilepsia. 50:16-18; Chen, et al., 2006, Lancet Neurol. 5:246-56; Wasterlain, et al., 2006, from Status Epilepticus: Mechanisms and management. MIT Press, Boston; Naylor et al., 2013, epublication PMID: 23313318) This maladaptive change increases glutamatergic excitation at a time when there is already too much excitation in the brain, resulting in the observed seizures.
Thus, there is a need in the art for compositions and formulations for treating nerve agent-induced seizures as well as “civilian” SE. The present invention satisfies this need.